Urinary ET-1 excretion after exposure to radio ...

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0.9 ± 0.1a. Iopamidol (non-ionic, low osmolar) or. Diatrizoate meglumine (ionic, high osmolar). 155 ± 2a. Before and 15 min after angiography. Plasma. +/?. 12.

LFS-13874; No of Pages 6 Life Sciences xxx (2014) xxx–xxx

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Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function Fabian Heunisch a, Gina von Einem a, Markus Alter a,b, Andreas Weist a, Thomas Dschietzig c,d, Axel Kretschmer e, Berthold Hocher f,⁎ a

Center for Cardiovascular Research, Charité, Berlin, Germany Department of Nephrology, Campus Benjamin Franklin, Charité, Berlin, Germany Immundiagnostik AG, Bensheim, Germany d Department of Cardiology and Angiology, Charité Campus Mitte, Berlin, Germany e Bayer Pharma AG, Wuppertal, Germany f Institute for Nutritional Science, University of Potsdam, Potsdam, Germany b c

a r t i c l e

i n f o

Article history: Received 1 November 2013 Accepted 31 December 2013 Available online xxxx Keywords: Urinary ET-1 Clinical study Radiocontrast media-induced nephropathy Kidney

a b s t r a c t Aims: Contrast media-induced nephropathy (CIN) is associated with increased morbidity and mortality. The renal endothelin system has been associated with disease progression of various acute and chronic renal diseases. However, robust data coming from adequately powered prospective clinical studies analyzing the short and long-term impacts of the renal ET system in patients with CIN are missing so far. We thus performed a prospective study addressing this topic. Main methods: We included 327 patients with diabetes or renal impairment undergoing coronary angiography. Blood and spot urine were collected before and 24 h after contrast media (CM) application. Patients were followed for 90 days for major clinical events like need for dialysis, unplanned rehospitalization or death. Key findings: The concentration of ET-1 and the urinary ET-1/creatinine ratio decreased in spot urine after CM application (ET-1 concentration: 0.91 ± 1.23 pg/ml versus 0.63 ± 1.03 pg/ml, p b 0.001; ET-1/creatinine ratio: 0.14 ± 0.23 versus 0.09 ± 0.19, p b 0.001). The urinary ET-1 concentrations in patients with CIN decreased significantly more than in patients without CIN (− 0.26 ± 1.42 pg/ml vs. − 0.79 ± 1.69 pg/ml, p = 0.041), whereas the decrease of the urinary ET-1/creatinine ratio was not significantly different (non-CIN patients: − 0.05 ± 0.30; CIN patients: − 0.11 ± 0.21, p = 0.223). Urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio were not associated with clinical events (need for dialysis, rehospitalization or death) during the 90 day follow-up after contrast media exposure. However, the urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application were higher in those patients who had a decrease of GFR of at least 25% after 90 days of follow-up. Significance: In general the ET-1 system in the kidney seems to be down-regulated after contrast media application in patients with moderate CIN risk. Major long-term complications of CIN (need for dialysis, rehospitalization or death) are not associated with the renal ET system. © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Introduction Besides chronic renal failure there are also studies indicating that the renal ET system might play a role in the pathogenesis of acute kidney injury. Ischemia–reperfusion injury by bilateral clamping of the renal pedicles for 30 min causes an up-regulation of ET-1 and the ETA receptor in wild-type animals with associated vascular and tubular injuries at 24 h after ischemia–reperfusion injury. Both measures were attenuated in animals with a deletion of vascular endothelial cell ET-1 gene ⁎ Corresponding author at: Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Potsdam, Germany. E-mail address: [email protected] (B. Hocher). URL: http://www.uni-potsdam.de/eem (B. Hocher).

expression suggesting that the renal ET system might be involved in the pathogenesis of acute kidney injury (AKI) (Arfian et al., 2012). Evidence that ET-1 may alter the intrarenal microcirculation in AKI — so supporting ET blockers as a potential therapeutic strategy in AKI — comes from a model of endotoxin-induced AKI. In this case, treatment with an ETA receptor antagonist attenuated the reduction in medullary blood flow independent of changes in systemic blood pressure and total renal blood flow (Fenhammar et al., 2011). Given that ET-1 has effects beyond simply altering vascular tone, other factors may mediate the benefits of ET receptor blockade. These include a reduction in oxidative stress and inflammation (Arfian et al., 2012; Gulmen et al., 2009). Thus the renal ET system might be critical in the control of microcirculation and oxidative stress during AKI and hence modulation AKI outcome.

http://dx.doi.org/10.1016/j.lfs.2013.12.233 0024-3205 © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

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F. Heunisch et al. / Life Sciences xxx (2014) xxx–xxx Check of the inclusion and exclusion criteria

Before: blood and urine collection

3 months after: Follow up with blood collection

24 hours after: blood and urine collection

// Hospitalization due to un stable or stable angina

CM application

Fig. 1. Study design.

A subtype of the AKI is the contrast-induced nephropathy (CIN) caused by iodinated radiocontrast media. This earnest complication after contrast media application causes about 10% of all in-hospital AKI (Nash et al., 2002). CIN goes along with a reduction of the glomerulary filtration rate (GFR) and an increase of the renal function marker creatinine and cystatin c, respectively. But there is no standardized definition of CIN yet (Barrett, 1994). In clinical studies there is a wide range in the change of the concentration (Cochran et al., 1983; Byrd and Sherman, 1979; Gomes et al., 1985) as well as in the observed time (Mason et al., 1985; VanZee et al., 1978). In recent studies mostly the definition “rise of 25% from baseline or 0.5 mg/dl within 48 h” was used. But also an increase of cystatin c can be “a reliable marker for the early diagnosis and prognosis of contrast-induced acute kidney injury” (Briguori et al., 2010). Meta-analyses of comparison of creatinine and cystatin c saw an advantage to cystatin c for earlier detection of changes in the GFR (Dharnidharka et al., 2002; Zhang et al., 2011). The combination of both markers to the definition of CIN was used, too (Poletti et al., 2007). There are a large number of possible risk factors for CIN. The most common ones are what Mehran et al. subsumed in a simple risk score for CIN (Mehran et al., 2004). It includes increased creatinine levels or impaired GFR, used volume of contrast media, diabetes mellitus, anemia, age, congestive heart failure, periprocedurally intra-aortic balloon pump and hypotension. In addition also the kind of CM could be a risk factor (Solomon et al., 2006). Combination of risk factors enhances the risk of a CIN above 57% (Mehran et al., 2004). Patients with CIN have a poorer prognosis. The risk of a complete loss of kidney function and the necessity of a dialysis rises with the risk of CIN (Mehran et al., 2004). Additional patients with CIN are at risk of a higher rate of all-cause mortality (Rihal et al., 2002). The pathogenesis of CIN is still unknown (Seeliger et al., 2012). Theories include direct damage of the endothelia (Hizoh et al., 1998; Andersen et al., 1994; Schick and Haller, 1999), induction of apoptosis (Fanning et al., 2002), medullar hypoxia (Heyman et al., 2008) and perturbation of the regulation of the renal blood flow (Sendeski et al., 2009). Currently there are only very few smaller studies analyzing the renal ET system in humans after exposure to contrast media. We thus analyzed in a large prospective clinical study the renal ET system before and after exposure to contrast media due to coronary angiography and followed the patients for 90 days for clinical events. Method Study population and protocol In a prospective study from January 2010 to December 2011 we included 327 patients with renal impairment (creatinine N 1.1 mg/dl) or diabetes mellitus (predescribed or HbA1c N 6.4%) undergoing a coronary angiography. Excluded were all patients without any inclusion criteria or with terminal kidney disease. Patients, who didn't give or weren't able to give their agreement were excluded, either. The design of the study is illustrated in Fig. 1. The treatment of the patients was not influenced in any case by this study. All patients got the triiodonated

non-ionic low-osmolar iobitridol (XENETIX® 350, Guerbet GmbH, Sulzbach/Taunus, Germany) as contrast media. If patients have a higher risk to develop CIN, the physician responsible for this patient gave 0.9% saline solution i.v. with (500 ml before and two times 500 ml after CM examination).

Sample treatment and measurement The samples were frozen at −80 °C the very same day. Before freezing blood samples were centrifuged 5 min with 3000 rotates per minutes and only the plasma was frozen. Creatinine was measured according to the method of Jaffé. Cystatin c was measured by an immunonephelometric method using polystyrene particles coated with human cystatin c specific antibodies (Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany). For the measurement of ET-1 a Quantikine ELISA (DET100, R&D Systems, Minneapolis, USA) was used. Its mean minimum detectable dose is 0.087 pg/ml. No significant cross-reactivity of this ELISA is detectable for Big Endothelin-1 (aa 16–38), Big Endothelin-2, Sarafotoxins S6b and-S6c. Endothelin-2 shows 23.4% cross-reactivity according to the manufacturer of the assay.

Definition of endpoints CIN was defined as an increase of creatinine of 25% or 0.5 mg/dl from the baseline within 48 h or an increase of cystatin c of 25% from the baseline within 24 h. Death is the subsumption of death of all causes. The endpoint dialysis is defined as every dialysis in the following three months after CM application. Non-elective hospitalization is Table 1 Baseline characteristics of the cohort. Patients' characteristics Female (%) / male (%) Age (±SD) Body mass index (±SD) CM-volume (±SD) Baseline creatinine (±SD) Baseline cystatin c (±SD) Baseline urinary ET-1 Baseline GFR Diabetes mellitus (%) Congestive heart failure (%) Coronary artery disease (%) Hypertension (%) Anemia (%) Hydration (%) Smoking (%) Diuretics (%) ACE inhibitors (%) ARB (%)

N years kg/m2 ml mg/dl mg/l pg/ml ml/min/1.73 m2

327 (100%) 75 (22.9%) / 252 (77.1%) 68.94 (±9.73) 29.04 (±5.51) 113.46 (±57.13) 1.24 (±0.45) 1.15 (±0.46) 0.91 (±1.23) 64.51 (±21.33) 175 (53.5%) 86 (26.3%) 235 (71.9%) 290 (88.7%) 90 (27.5%) 177 (54.1%) 50 (15.3%) 206 (63.0%) 178 (54.4%) 107 (32.7%)

CM: contrast media, GFR: glomerulary filtration rate according to the MDRD formula, SD: standard deviation, ACE: angiotensin converting enzyme, ARB: angiotensin receptor blocker.

Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

F. Heunisch et al. / Life Sciences xxx (2014) xxx–xxx

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Table 2 ET-1 before and 24 h after contrast media application. ET-1 before

Whole cohort CIN Dialysis Non-elective hospitalization Death Decrease of GFR of ≥25% (90 days)

No Yes No Yes No Yes No Yes No Yes

N

Mean (±SD)

327 255 38 277 12 237 48 279 9 209 22

0.91 (±1.23) 0.91 (±1.19) 1.21 (±1.75) 0.92 (±1.23) 0.64 (±0.50) 0.83 (±1.03) 1.32 (±1.84) 0.92 (±1.23) 0.46 (±0.28) 0.87 (±1.14) 1.30 (±1.88)

ET-1 24 h after p 0.167 0.431 0.082 0.255 0.671

N

Mean (±SD)

313 244 39 265 11 229 44 268 8 200 20

0.63 (±1.03) 0.68 (±1.14) 0.46 (±0.45) 0.60 (±0.97) 0.85 (±1.49) 0.58 (±0.92) 0.68 (±1.31) 0.61 (±1.01) 0.52 (±0.65) 0.55 (±0.91) 1.27 (±1.92)

Change of ET-1 p 0.236 0.400 0.522 0.810 0.036

N

Mean (±SD)

300 239 37 254 11 221 42 257 8 197 17

−0.33 (±1.42) −0.26 (±1.42) −0.79 (±1.69) −0.38 (±1.36) 0.20 (±1.58) −0.30 (±1.19) −0.74 (±2.04) −0.37 (±1.39) 0.10 (±0.54) −0.35 (±1.25) −0.52 (±2.14)

p 0.041 0.167 0.176 0.343 0.920

ET-1: urinary endothelin, uCr: urinary creatinine, CIN: contrast-induced nephropathy, GFR: glomerulary filtration rate according to the MDRD formula, SD: standard deviation.

every hospital stay for any reason, which was not preplanned at study entry.

however, higher in those patients who had a decrease of GFR of at least 25% after 90 days of follow-up (Tables 2 and 3).

Statistical analyses

Discussion

The statistical analyses were made with SPSS 20 (IBM® SPSS® Statistics IBM Cooperation, Armonk, USA). Differences among the biomarkers were estimated with Student's t-test for independent or t-test for dependent variables.

This prospective study with 327 participants showed a significant decrease of the urinary endothelin concentration as well as the urinary ET-1/creatinine ratio after CM application. Death (all cause mortality), need for permanent or transient dialysis or rehospitalization during the follow-up of 90 days after CM application was not associated with urinary ET-1 concentrations — neither before nor after CM exposure. The urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application, however, were higher in those patients who had a decrease of GFR of at least 25% after 90 days of follow-up.

Results Details of the study population are shown in Table 1. There was no difference in the ET-1 concentration at any time between groups with diabetes mellitus, congestive heart failure, coronary artery disease, hypertension, hydration or smoking and the groups without these risk factors (p N 0.05 for all). The concentration of ET-1 and the urinary ET-1/creatinine ratio decreased in spot urine after CM application (ET-1 concentration: 0.91 ± 1.23 pg/ml versus 0.63 ± 1.03 pg/ml, p b 0.001; ET-1/ creatinine ratio: 0.14 ± 0.23 versus 0.09 ± 0.19, p b 0.001). The urinary ET-1 concentrations in patients with CIN decreased significantly more than in patients without CIN (− 0.26 ± 1.42 pg/ml vs. − 0.79 ± 1.69 pg/ml, p = 0.041), whereas the decrease of the urinary ET-1/creatinine ratio was not significantly different (non-CIN patients: −0.05 ± 0.30; CIN patients: −0.11 ± 0.21, p = 0.223). Urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio were not associated with clinical events (need for dialysis, rehospitalization or death) during the 90 day follow-up after contrast media exposure (see also Tables 2 and 3). The concentration of ET-1 and the urinary ET-1/creatinine ratio in spot urine 24 h after CM application were,

Urinary endothelin concentrations in humans after CM application Few studies analyzed ET-1after CM application yet. An overview is shown in Table 4. The total number of patients analyzed is far less than the number of patients in our study. Ulas et al. (2013). showed an increase in the urinary as well as in the plasma ET-1 concentrations in only 78 patients. It is of note that the applied contrast media volume was much higher in this study as compared to our study (192 ml vs. 113 ml). However, CM volume matters. This was shown by Clark et al. (1997). They divided their patients into two groups. One got less than 150 ml, the other more than 150 ml CM. Only the group with more than 150 ml had an increase of the ET-1 level. In the small study by Fujisaki et al. (2003) about 100 ml CM were used. They studied two groups, one with normal creatinine levels, the other one with very high levels (2.5 ± 0.5 mg/dl (mean ± SEM)). Only the group with poor renal function had an increase of urinary ET-1 concentrations.

Table 3 ET-1/urinary creatinine ratio before and 24 h after contrast media application. ET-1/uCr ratio before

Whole cohort CIN Dialysis Non-elective hospitalization Death Decrease of GFR* of ≥25% (90 days)

No Yes No Yes No Yes No Yes No Yes

N

Mean (±SD)

326 254 38 276 12 236 48 278 9 208 22

0.14 (±0.23) 0.14 (±0.25) 0.17 (±0.24) 0.14 (±0.24) 0.22 (±0.21) 0.14 (±0.24) 0.18 (±0.22) 0.14 (±0.24) 0.14 (±0.19) 0.14 (±0.26) 0.20 (±0.25)

ET-1/uCr ratio 24 h after p 0.526 0.263 0.276 0.950 0.387

N

Mean (±SD)

312 244 38 264 11 228 44 267 8 200 19

0.09 (±0.19) 0.10 (±0.21) 0.06 (±0.08) 0.08 (±0.15) 0.24 (±0.52) 0.08 (±0.18) 0.10 (±0.20) 0.08 (±0.15) 0.25 (±0.60) 0.07 (±0.14) 0.20 (±0.30)

Change of ET-1/uCr ratio p 0.247 0.323 0.504 0.465 0.002

N

Mean (±SD)

p

300 239 37 254 11 221 42 257 8 197 17

−0.06 (±0.28) −0.05 (±0.30) −0.11 (±0.21) −0.07 (±0.27) 0.01 (±0.45) −0.06 (±0.28) −0.09 (±0.24) −0.07 (±0.27) 0.10 (±0.42) −0.07 (±0.29) −0.06 (±0.30)

b0.001* 0.223 0.590 0.518 0.083 0.664

ET-1: urinary endothelin, uCr: urinary creatinine, CIN: contrast-induced nephropathy, GFR: glomerulary filtration rate according to the MDRD formula, SD: standard deviation, *test for dependent variables.

Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

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Study

N

Baseline creatinine [mg/dl]

Used CM

CM volume [ml]

Endothelin measurements

Kind of samples

Changes of endothelin concentration (plasma/urine)

Clark et al. (1997)

7 (with high doses) 12 (with low doses) 8 (with renal failure and/or DM) 6 (with renal impaired function) 6 (controls) 11 40 with CAD 40 controls 78

0.9 ± 0.1a 1.1 ± 0.04a

Iopamidol (non-ionic, low osmolar) or Diatrizoate meglumine (ionic, high osmolar)

155 ± 2a 82 ± 11a

Before and 15 min after angiography

Plasma

+/? 0/?

Before and 1, 2 and 3 days after CM examination Before and 30 min after cardiac catheter Before and 1, 2 and 3 days after CM examination Before and 24 h after PCI

Plasma and urine

Fujisaki et al. (2003) Simon et al. (2003) Chai et al. (2010) Ulas et al. (2013)

2.12 ± 0.3a 2.5 ± 0.5a 0.8 ± 0.1a ? ? (without renal failure)

Iopromid (non-ionic, low osmolar) ?

112 ± 15a 98 ± 18a 100 ± ?a 70–100 ml ?

0.76 ± 0.12b

Iobitridol (non-ionic, low osmolar)

192 ± 78b

?

Plasma Plasma Plasma and urine

+/? 0/+ 0/0 0/? +/? ?/? +/+

N: number of participants of the study, CM: contrast media, DM: diabetes mellitus, CAD: coronary artery disease, PCI: percutaneous coronary intervention, +: significant increase, 0: no significant change. a Mean ± standard error of the mean. b Mean ± standard deviation.

Table 5 Overview over animal studies testing ET receptor blockers in CM administration. Study

Model

Used CM/medication for CIN

Read out

Kind of ET-1 blockade

Effect of ET-1 blockade

Cantley et al. (1993)

Rats

Renal blood flow, urine flow rate

CP170687 (non-selective)

Brooks and DePalma (1996)

Dogs

Renal blood flow, renal resistance

SB209670 (non-selective)

Bird et al. (1996)

Rats

GFR, RPF, diuresis, necrosis

Pollock et al. (1997)

Rats

SB209670 (non-selective), BMS-182,874 (ET-A receptor antagonist) A-127722 (ET-A receptor antagonist)

Can't prevent drop of renal blood flow in normal rats, urine flow like placebo Abolishes the increase of the renal resistance and decrease of renal blood flow GFR less reduced, urinary flow reduced, RPF without change, less morpho logic necrosis, selective and non-selective blockade equivalent Reduction of protein excretion and plasma creatinine

Liss et al. (2003)

Rats

Iothalamate (ionic high-osmolar CM), indomethacin Diatrizoate (ionic high-osmolar CM), indomethacin Iopamidol (non-ionic low-osmolar CM), indomethacin, L-NAME Diatrizoate (ionic, high-osmolar CM), (Indomethacin, L-NAME) Iopromide (non-ionic, low-osmolar CM),

Protein excretion, plasma creatinine Renal CBF, OMBF, pO2

BQ123 (ET-A receptor antagonist), BQ788 (ET-B receptor antagonist)

No effect on CBF and OMBF, less reduction of pO2 with BQ123

CM: contrast media, ET: endothelin, MAP: mean arterial blood pressure, L-NAME: N-nitro-L-arginine-methylester, ET: endothelin, GFR: glomerulary filtration rate. RPF: renal plasma flow, CBF: cortical blood flow, OMBF: outer medullary blood flow: pO2: outer medullary oxygen tension.

F. Heunisch et al. / Life Sciences xxx (2014) xxx–xxx

Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

Table 4 Overview over human studies with endothelin measurements after CM application.

F. Heunisch et al. / Life Sciences xxx (2014) xxx–xxx

Thus differences in applied CM volume and degree of preexisting renal failure might explain our findings. There is obviously a critical CM volume threshold. Above this threshold, CM seems to be directly toxic to the kidney and ET-1 rises. If the patients get less volume, only CM related hemodynamic effects occur. CM are for example osmotic diuretics and hence might cause transient hypotension contributing to the pathogenesis of CIN. Urinary ET-1 and 90-day outcome after CM exposure In our study hard endpoints such as death (all cause mortality), need for permanent or transient dialysis or rehospitalization during the follow-up of 90 days after CM application was not associated with urinary ET-1 concentrations — neither before nor after CM exposure. Yip et al. (2005) investigated 186 patients with ST-elevated myocardial infarction undergoing percutaneous coronary interventions. These 186 patients were divided in two groups, dependent on their endothelin level in the plasma. In addition these two groups vary in age, reperfusion time and the incidence of the left ventricular ejection fraction. Patients with higher endothelin concentration (older, higher perfusion time and less LVEF) had a higher mortality within 30 day μs after the intervention. Unfortunately there was no information about the kidney function of these patients. Nevertheless, this study showed a positive relationship between the endothelin levels, risk factors and the mortality. Most likely, patients in this study were sicker — see above. This study rather describes the relationship between an activated ET system and mortality due to ST-elevated myocardial infarction then the relationship between CM exposure and death. The leading event was the ST-elevated myocardial infarction in this study. This study is thus not a real CIN study. The decrease of both urinary ET-1 as well as the urinary ET-1/ creatinine ratio in the entire study population in our study fits very well with a recent clinical trial. In this prospective placebo controlled clinical study Wang et al. (2000) investigated 158 patients with chronic renal insufficiency and undergoing cardiac angiography and they were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. The primary end point was the mean change in serum creatinine concentration from baseline at 48 h; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of ≥0.5 mg/dl (44 μmol/l) or ≥ 25% from baseline within 48 h of radiocontrast administration. The mean increase in serum creatinine 48 h after angiography was higher in the SB 209670 than in the placebo group. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, p = 0.002). This negative effect of SB 209670 was apparent in both diabetic and non-diabetic patients. Thus, blocking the ET system was harmful after CM exposure. This fits to a certain extent to the observation that patients have in our study. Both blocking the ET system with ET receptor antagonists as well as reduced excretion of ET after CM might be due to hemodynamic changes after CM exposure in terms of blood pressure reduction. A fall in blood pressure, however, increases the risk of CIN. This hypothesis needs for sure be tested in further studies. Once again, this needs to be tested in future studies. It is of note in this context that there are a couple of promising animal studies suggesting that blockade of ET receptors — either with ETA selective agents or combined ETA/ETB receptor antagonists might be useful to prevent CIN, see Table 5. These preclinical studies were the basic for the abovementioned clinical study. It is important to know in this context that a long list of drugs including selective and non-selective ET receptor blockers work in animal models of various types of acute renal failure — however, none of these drugs was ever approved from European or US authorities. This indicates that animal models in the case of acute renal failure are of very limited clinical value and were so far not helpful to develop a drug to prevent CIN. Why these models are of such a limited translational value is poorly

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understood. Maybe they are not close enough to the human situation: Patients getting CIN are typically elderly, have diabetes, heart failure, atherosclerosis, and preexisting renal failure due to chronic renal failure. The animal models are typically young rodents without any co-morbidity. Renal failure is induced in these models with pharmacological tool such as indomethacin etc. These animal models are obviously far away from the human situation. It is thus no surprise that data coming from these experiments cannot be translated successfully to the human situation. We urgently need good translational animal models of CIN. Our clinical study showed that the urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application were higher in those patients who had a decrease of GFR of at least 25% after 90 days of follow-up — means the activations of the renal ET system after contrast media-induced AKI related long-term chronic alterations of kidney function. This fits nicely to a recent animal study ischemia-induced AKI in rats showing that long-term activation after ischemic AKI leads to chronic renal failure (Zager et al., 2013). This study is the by far the largest clinical prospective observational study in the field. We presented short term outcomes (CIN) and longterm outcomes such as change of GFR after 3 months, death, need for dialysis and rehospitalization during follow-up of 90 days in relationship to urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio before and 24 h after contrast media exposure. Given the unexpected finding of a significant decrease of the urinary endothelin concentration as well as the urinary ET-1/creatinine ratio after CM application, this study needs to be replicated in an independent second equally sized clinical study. We need to acknowledge that it is a clear study limitation that we did not measure plasma ET-1 concentrations. Conclusion Urinary ET-1 and the urinary ET-1/creatinine ratio decrease after CM application. There was no obvious relationship between ET-1 levels and hard outcome such as death or need for dialysis after three months of follow-up. Only a decrease of GFR N 25% after 90 days of follow-up was associated with higher urinary ET-1 concentrations as well as ET1/creatinine ratios. Conflict of interest None of the authors has a conflict of interest with regard to this paper.

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Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

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Please cite this article as: Heunisch F, et al, Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function, Life Sci (2014), http://dx.doi.org/10.1016/j.lfs.2013.12.233

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